Transdermal therapeutic system for administering lipophilic and/or sparingly skin-permeable active substances

ABSTRACT

A transdermal therapeutic system for administering lipophilic, poorly water-soluble and/or sparingly skin-permeable pharmaceutical active substances. The active substance is present in a multi-component enhancer system consisting of 4 components and each component of the multi-component enhancer system is selected from a different one of the substance groups: a) terpenes, b) cyclic glucitol ethers, c) medium-chain triglycerides of capric and caprylic acid and/or of linoleic acid; and d) longer-chain alcohols having a chain length of 8 or more carbon atoms.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of co-pending U.S.application Ser. No. 12/083,888 filed on Apr. 21, 2008, which is aNational Stage application of International Application No.PCT/EP2006/009570, filed on Oct. 4, 2006, which claims priority ofGerman application number 10 2005 050 431.0, filed on Oct. 21, 2005, allof which are incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a transdermal therapeutic system forthe administration of lipophilic, poorly water-soluble and/or sparinglyskin-permeable pharmaceutical active substances. More particularly, thepresent invention relates to a transdermal therapeutic liquid reservoirsystem for administration of vinpocetine, moxonidine, pergolide or oneof their pharmaceutically acceptable salts.

2. Description of the Prior Art

Vinpocetine (ethyl apovincamin-22-oate; 3α16α-apovincaminic acid ethylester; ethyl-12-desoxy-12,13-didehydro-vincanol-12-carboxylate) (CAS-No.42971-09-5) is a pharmaceutical active substance with antioxidant,vasodilating and neuro-protective action which is used for symptomatictreatment of chronic, cerebro-organically caused impairments ofperformance in the form of impaired memory, impaired concentration,blocking of thought processes, affective disturbances, prematurefatigability as well as lack of drive and lack of motivation. Atpresent, this active substance is available on the market only as anoral administration form (tablets) containing 20 mg vinpocetine in theform of its free base—under the brand name CAVINTON®. However, theabsorption quota of vinpocetine in a fasting state is only about 6 to 7percent. Taken during meals, absorption improves by 60 to 100 percent.In both cases, vinpocetine enters the blood stream about half an hourafter its administration. With oral administration, its eliminationhalf-life is one to two hours; within eight hours vinpocetine will havebeen excreted by the body almost completely. In summary, it is to benoted that the bioavailability of orally administered vinpocetine isvery poor.

To improve the bioavailability of vinpocetine, a transdermal applicationwith the aid of a transdermal therapeutic system could be taken intoconsideration. However, the physicochemical properties of vinpocetineare unfavourable for transdermal application. Thus, the partitioncoefficient log P_(Octanol/Water) of about 3.9 and the poorwater-solubility of 0.02 μg/ml at room temperature characterisevinpocetine as a very lipophilic pharmaceutical active substance.

Kobayashi, D. et al. (Biol. Pharm. Bull., 16, (1993) 254-258) describethat is possible to achieve a permeation rate of 6.45 μg/cm²×h with anactive substance/enhancer mixture, in the form of a 1% suspension ofvinpocetine in a mixture of ethanol and 1-menthol, which was appliedin-vitro directly to human full-thickness skin. However, this liquidpreparation does not enable a continuous release of active substance,but has to be repeatedly applied in order to achieve an almost constantplasma level of vinpocetine over the day. Therefore, such a liquidadministration form is likely to meet with little acceptance amongpatients.

SUMMARY OF THE PRESENT INVENTION

The first preliminary tests carried out in accordance with the presentinvention with a view to developing a matrix transdermal therapeuticsystem for administration of vinpocetine led to transdermal therapeuticsystems (TTSs) by means of which a skin flux (permeation rate in steadystate) of 0.91 μg/cm²×h could be achieved. In order to adjust thetherapeutically required concentration of 2 to 3 ng/ml of vinpocetine ina patient's plasma, a transdermal therapeutic system that is designedfor an application period of 24 hours would have to have an area ofabout 120 cm². For reasons of patient acceptance, however, the surfacearea of a transdermal therapeutic system should be kept as small aspossible and, if possible, should not exceed 40 cm², preferably 20 cm².

The task initially underlying the invention thus consisted in providinga transdermal therapeutic system for administration of vinpocetine whichhas an acceptable size of not more than 40 cm². In other words, the taskconsisted in developing a transdermal therapeutic system foradministration of vinpocetine by means of which it is possible toachieve a permeation rate of at least 2.15 μg/cm²×h, preferably at least5.0×h, which corresponds to a transdermal delivery rate of 2 mg/day.With such a high delivery rate or daily dose, it could be possible toachieve the therapeutically required plasma level of 2 to 3 ngvinpocetine per milliliter of plasma.

Surprisingly, this task is achieved by a liquid reservoir system whereinvinpocetine is present dissolved or suspended in a multi-componentenhancer system, said enhancer system consisting of 4 permeationenhancers (=components of the enhancer system) and each component ofsaid enhancer system being selected from a different one of thefollowing substance groups:

a) terpenes

b) cyclic glucitol ethers

c) medium-chain triglycerides of capric and caprylic acid and/or oflinoleic acid; and

d) longer-chain alcohols.

In further tests carried out in accordance with the present invention,it emerged, surprisingly, that the enhancer system according to thepresent description can be advantageously utilised also in connectionwith other active substances which are similar to vinpocetine in termsof their physicochemical properties, that is, lipophilic, poorlywater-soluble and/or sparingly skin-permeable active substances.

Thus, the present invention relates to transdermal therapeutic systemsfor administering lipophilic, poorly water-soluble and/or sparinglyskin-permeable pharmaceutical active substances.

“Lipophilic”, as used in this description, means that the activesubstance has a high tendency to migrate into a water-immiscible phase.Lipophilic substances are characterized by a high log P value. The log Pvalue is the partition coefficient of a substance between octanol andwater: C_(Octanol)/C_(Water).

“Poorly water-soluble” active substance, as used in the presentdescription, are those active substances which possess a solubility inwater of less than 0.3%-wt., i.e. substances less than 3 mg of which canbe dissolved in one milliliter of water.

The expression “sparingly skin-permeable”, as used in the presentdescription, describes active substances whose flux alone, i.e. withoutpermeation enhancers or other measures to increase skin permeation, istoo low to be able to achieve the active substance concentration in theplasma necessary in order to attain a therapeutic effect. Generally,those active substances having a molecular weight >(“greater than”) 500or a log P of less than −1 or above 4 are regarded as sparinglyskin-permeable.

Lipophilic, poorly water-soluble active substances are as a rulecharacterized by poor bioavailability when administered orally.Transdermal administration of active substances which are poorlybioavailable when administered orally is basically conceivable, it istrue, but lipophilic active substances usually also belong to thesparingly or poorly skin-permeable active substances.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the accumulated permeation rates ofvinpocetine, in accordance with the present invention.

FIG. 2 is a graph showing the cumulated permeation rates of moxonidine,in accordance with the present invention.

FIG. 3 is a graph showing the cumulated permeation rates of pergolide,in accordance with the present invention.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

A preferred active substance which by means of the enhancer system ofthe invention can be administered via the skin with a permeation ratesufficient for therapeutic purposes is moxonidine.

Moxonidine(4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methyl-5-pyrimidinamine;4-chloro-6-methoxy-2-methyl-5-(2-imidazolin-2-yl)aminopyrimidine)(CAS-No. 75438-57-2) is an imidazole derivative which is recommended foressential hypertonia. It is available as CYNT® film tablets orPHYSIOTENS® film tablets. Moxonidine is gastrointestinally well-absorbedand not metabolised presystemically, so that its bioavailability isabout 90%. Moxonidine does, however, have a half-life of only 2 to 3hours and is excreted substantially via the kidneys. The daily dosenecessary is about 0.2 to 0.6 mg; the effective plasma level is around5.4 ng/ml (according to Farsang, C., J. Clin. Basic Cardiol. 4, (2001),197). An advantageous effect of moxonidine is that it lowers theincreased activity of the sympathetic tone in renal insufficiency.However, compared to the dose for a person with healthy kidneys, in thecase of renal insufficiency the maintenance dose of moxonidine must belowered and/or the dosage interval extended.

Among the clinically useful antihypertensive active substances,moxonidine is the one that has the lowest basicity. At a pH value of7.4, only about 50% of moxonidine is present in cationic form.Moxonidine is a lipophilic active substance; it has a very lowsolubility in water, but is soluble up to 100 mM in ethanol or DMSO. Thewater solubility of moxonidine (base) is 1.36 mg/ml at 22° C. Itspartition coefficient log P_(Octanol/Water) is −1.3. These two valuescharacterise moxonidine (the free base) as a poorly water-soluble andsparingly skin-permeable substance.

A further active substance that can be administered via the skin withthe aid of the inventive enhancer system at a permeation rate sufficientfor therapeutic purposes is pergolide.

Pergolide ((8

β-8-[(methylthio)methyl]-6-propyl-ergoline, D-6-n-propyl-8β-methyl-mercaptomethyl-ergoline) (CAS-No. 66104-22-1) is asemisynthetic ergoline with strong dopamine(D)-2-agonistic and a lowerD-1-receptor-agonistic action which is approved for the treatment ofParkinson's disease. Although the chemical structure of pergolide isdifferent from that of dopamine, it does act on the same binding sitesas dopamine. Moreover, it does also have an effect in lowering theprolactin concentration in the plasma. The plasma half-life of pergolideafter oral administration is 27 hours. The daily dose is about 5 mg(Gerschlager, W., J. Neurol. Neurochem. Psychiatr., 5, (2004), 21-24).The water-solubility of pergolide (base) is 0.021 μg/ml at 22° C. Itspartition coefficient log P_(Octanol/Water) is about 4.02. These twovalues characterise the pergolide base as a very poorly water-solubleand sparingly skin-permeable substance.

Because of their ionic character, also the pharmacologically acceptablesalts of vinpocetine, moxonidine and pergolide are counted among thesparingly skin-permeable substances, even though their water-solubilityis higher than that of vinpocetine, moxonidine or pergolide,respectively. Therefore, the pharmacologically acceptable salts ofvinpocetine, the pharmacologically acceptable salts of moxonidine andthe pharmacologically acceptable salts of pergolide also belong to thesubstances or active substances that can be transdermally administeredwith the inventive multi-component enhancer system at a permeation ratethat is sufficient for therapeutic purposes. Examples of known salts ofthe active substances mentioned are moxonidine hydrochloride andpergolide mesylate.

Transdermal therapeutical liquid reservoir systems as such, whereina—generally liquid—active substance preparation is contained in a bagformed of a release-controlling membrane and a—preferably activesubstance-impermeable—are known to those skilled in the art. In thesesystems, pharmaceutically acceptable and skin-tolerated organic solventsserve as carrier medium whose viscosity can be adjusted with suitableauxiliary substances (e.g. mineral oils) to meet the respectivetechnological requirements. Ideally, the solvents used also possessproperties promoting the permeation of the active substance through thepatient's skin. However, substances promoting the permeation of theactive substance, so-called enhancers, may be added to the solvent. Inaddition, the liquid reservoir systems comprise a pressure-sensitiveadhesive layer by which the system is attached to the patient's skin.

In the liquid reservoir system according to the invention, thelipophilic, poorly water-soluble and/or sparingly skin-permeable activesubstance is present in a multi-component enhancer system in dispersedor suspended form, said enhancer system consisting of four enhancerswhich increase the permeation of the active substance. Each of theenhancers of said multi-component enhancer system comes from a differentgroup of substances. The substance groups from which the enhancers areselected are:

a) terpenes;

b) cyclic glucitol ethers;

c) triglycerides of capric and caprylic acid and/or of linoleic acid;and

d) longer-chain alcohols.

Terpenes can be derived from isoprene or from isopentenyl units, whichmeans that the number of the carbon atoms contained in their skeletalstructure can be divided by 5. According to the number of isopreneresidues, a distinction is drawn between monoterpenes (C₁₀),sesquiterpenes (C₁₅), diterpenes (C₂₀), sesterterpenes (C₂₅),triterpenes (C₃₀), tetraterpenes (C₄₀) and polyterpenes. Furthermore,there also are naturally occurring terpenes whose structure is not inkeeping with the isoprene rule. The terpenes are a heterogenic group ofcompounds which, due to their different functional groups, can beassigned to different substance groups, so that terpenes are consideredto include both hydrocarbons as well as the alcohols, ketones, aldehydesand esters that are derived therefrom.

In accordance with the invention, preference is given to monoterpenes,that is, terpenes made up of two isoprene units. Examples ofmonoterpenes are pinene, nerol, citral, camphor, menthol, carvacrol,thymol and limonene.

The monoterpenes can be divided into acyclic, monocyclic and bicyclicmonoterpenes. The acyclic monoterpenes include, for example, myrcene,ocimene and cosmene. Especially preferred are, in accordance with theinvention, the monocyclic monoterpenes which have a cyclohexane skeletonand can thus be derived from p-menthane.

Mostly, the monocyclic monoterpenes with cyclohexane skeleton are inturn divided according to their secondary allocation to substancegroups. Especially preferred are alcoholic monocyclic monoterpenes withcyclohexane skeleton, especially eucalyptol.

Particularly suitable as the cyclic glucitol ether is dimethylisosorbide. Glucitol, also called sorbitol, is the sugar alcohol ofglucose.

Amongst the triglycerides of capric and caprylic acid and/or of linoleicacid, those are used with preference which are sold under the brand nameMIGLYOL®, preferably MIGLYOL® 808, MIGLYOL® 810 and MIGLYOL® 812, withMIGLYOL® 812 being particularly preferred.

Used as the longer-chain alcohols are those alcohols having a chainlength of at least 8 carbon atoms, preferably at least 12 carbon atoms,preferably monohydric alcohols, especially preferably 1-dodecanol.

In a preferred embodiment, the components of the multi-componentenhancer system are present in a mixing ratio wherein the proportion ofthe component used in the lowest dose is at least 10%-wt. and theproportion of the most highly dosed component is maximally 40%-wt., eachrelative to the overall weight of the multi-component enhancer system.

The most highly preferred multi-component enhancer system is made up asfollows:

a) 25%-wt. eucalyptol as terpene;

b) 25%-wt. dimethyl isosorbide as cyclic glucitol ether;

c) 35%-wt. miglyol 812 as medium-chain triglyceride of caprylic andcapric acid; and

d) 15%-wt. 1-dodecanol as longer-chain alcohol with a chain length of 12carbon atoms or more.

The proportion of active substance in the active substance-containingpreparation amounts to 0.1 to 50%-wt., preferably 5 to 25%-wt.

The preparation contained in the liquid reservoir thus comprises theactive substance, which may be present in the multi-component enhancersystem in dissolved, dispersed or suspended form. In addition, theactive substance preparation may contain further substances by which therelease of active substance—in the sense of a retarded release—can becontrolled. Absorption agents are an example of those substances.

The absorption agents may be selected from the group containingcyclodextrins, polyvinyl pyrrolidone and cellulose derivatives.

The active substance preparation may additionally containviscosity-increasing auxiliary substances that do not have arelease-controlling function. The viscosity-increasing auxiliarysubstance is preferably selected from the group consisting of finelydispersed silicon dioxide, preferably AEROSIL R974®, polyacrylic acids,e.g. CARBOPOL 934®, mineral oils, wool waxes and high-molecularpolyethylene glycols. An example of a preferred polyethylene glycol isCARBOWAX 1000®. The active substance preparation may be present in theliquid reservoir as a solution, dispersion, suspension, paste or gel.

In the transdermal therapeutic system according to the presentinvention, the release of the active substance and of the enhancers fromthe liquid reservoir system can be controlled via:

the type of control membrane used, for example via its chemicalcomposition and/or the pore size;

the type of the pressure-sensitive adhesive layer used below the controlmembrane, by which the system is attached to the skin, for example viathe chemical composition and/or the layer thickness of said adhesivelayer;

a retarded delivery, achieved by the use of absorption agents in theliquid reservoir, for example of cyclodextrins, polyvinyl pyrrolidonesor cellulose derivatives.

As control membrane, microporous polymer films may be utilised which areproduced with a defined pore size and are made of polyethylene,polypropylene, polyurethane, copolymers of ethylene and vinyl acetate,and silicones. These polymer films are suitable provided that they areresistant to the substances contained in the active substancepreparation.

As pressure-sensitive adhesives which have properties that control therelease of the pharmaceutical active substance, and which are attachedbelow the control membrane for fixing the system on the skin, thosepressure-sensitive adhesives are preferred as are based on copolymers ofethylene and vinyl acetate, in combination with adhesive resins andadditives. With these pressure-sensitive adhesives, the penetrability orpermeability of the pressure-sensitive adhesive layer can be adjustedvia the ratio of ethylene to vinyl acetate. Also preferred arepressure-sensitive adhesives based on silicones since these arepermeable to most of the active substances and auxiliary substances, aswell as pressure-sensitive adhesives based on poly(meth)acrylates, andpressure-sensitive adhesives based on polyisobutylenes.

In the following, the invention will be illustrated in more detail bymeans of examples; these examples should, however, not be understood asbeing the only combinations for which protection is sought by thepresent application.

Examples 1 to 4

To prepare the pressure-sensitive adhesive liquid reservoir systems asspecified in more detail in Table 1, first, an active substance-freepolyacrylate adhesive solution of the DUROTAK® 1050 type (NationalStarch, Antwerp) or a copolymer of ethylene and vinyl acetate withaddition of an adhesive resin based on colophony (FORAL® 85 B) is spreadwith a wet-layer thickness of 300 μm on a siliconised polyethyleneterephthalate film with the aid of a doctor knife.

Subsequently, the solvents were withdrawn by drying the coated film forhalf an hour at 50° C. in a drying cupboard with a waste air duct. Thesolvent-free and active substance-free adhesive film was then coveredwith a 35-μm-thick polyurethane film (OPRAFLEX®, Lohmann) or with apolypropylene film by laminating, said film later serving as the controlmembrane. Onto this control membrane was placed a polyester film(SCOTCHPAK® No. 1220, 3M) and sealed to form bags having a roundreservoir of a diameter of 25 mm, using a special sealing mask heated bya commercial electric iron.

Via an existing orifice leading to the reservoir, the respectivevinpocetine/enhancer mixture—the enhancer components of which hadpreviously been mixed together in their respective weightpercentages—was filled into the reservoir using a syringe. The amount ofvinpocetine was 10%-wt., relative to the overall weight of the activesubstance/enhancer mixture. Following the filling of the reservoir, thefilling orifice was welded using an electric iron, so that a completelyclosed and storage-stable liquid reservoir system was obtained

Comparative Example 1

A matrix transdermal therapeutic system was prepared as a reference forthe vinpocetine-containing liquid reservoir systems by dissolvingOPPANOL® B 10 and OPPANOL® B 100, medium-molecular and high-molecularpolyisobutylenes from BASF in different mixing ratios in special boilingpoint gasoline of type 80/110, and subsequently dispersing therein2%-wt. vinpocetine and 17%-wt. lauryl lactate as enhancers. By stirringfor 30 minutes, a homogenous distribution of the active substancecrystals in the adhesive solution was achieved. This was followed bydegassing the dispersion in an ultrasound bath for 10 to 15 minutes.

To produce the self-adhesive, active substance-containing film, asiliconised polyethylene terephthalate film was coated with the activesubstance-containing adhesive material in a wet layer thickness of 400μm with the aid of a manual doctor-knife. The air from around theadhesive coating was exhausted for 20 minutes at room temperature,before the coating was dried for 10 minutes at 70° C.

The solvent-free, active substance-containing and self-adhesive coatingwas subsequently covered with a 15-μm-thick polyethylene terephthalatefilm by laminating.

Examples 5 and 6

Pressure-sensitive adhesive liquid reservoir systems for administrationof moxonidine were produced in accordance with the method indicated forExamples 1 to 4, by spreading and drying an active substance-freepolyacrylate adhesive solution and subsequently covering same with a35-μm-thick polyurethane film (OPRAFLEX®, Lohmann), as the controlmembrane, by laminating. A polyester film was placed on the controlmembrane and sealed with the special sealing mask to form bags which hada round reservoir of a diameter of 25 mm.

Via an existing orifice leading to the reservoir, the respective activesubstance/enhancer mixture containing 10%-wt. moxonidine was filled by asyringe into the reservoir, which was subsequently sealed, so that acompletely closed and storage-stable liquid reservoir system wasobtained.

Comparative Example 2

As comparative example for the moxonidine-containing liquid reservoirsystems, a matrix transdermal therapeutic system was produced thatconstituted a transdermal therapeutic system with permeation enhancerwhich was already optimised for the transdermal administration ofmoxonidine.

Examples 7 and 8

Pressure-sensitive adhesive liquid reservoir systems for theadministration of pergolide were produced in accordance with the methodindicated for Examples 1 to 4 by spreading and drying an activesubstance-free polyacrylate adhesive solution and thereafter coveringsame with a 35-μm-thick polyurethane film (OPRAFLEX®, Lohmann), whichserves as a control membrane, by laminating. A polyester film was placedon the control membrane and sealed with the special sealing mask to formbags which had a round reservoir of a diameter of 25 mm.

Via an existing orifice leading to the reservoir, the respective activesubstance/enhancer mixture containing 10%-wt. pergolide was filled by asyringe into the reservoir, which was subsequently sealed, so that acompletely closed and storage-stable liquid reservoir system wasobtained.

Comparative Example 3

As comparative example for the pergolide-containing liquid reservoirsystems, a matrix transdermal therapeutic system was produced thatconstituted a transdermal therapeutic system with permeation enhancerwhich was already optimised for the transdermal administration ofpergolide.

Determination of the permeation rates: The permeation rates of theaforementioned systems were determined in the in-vitro diffusion modelof “human epidermis” with the aid of modified Franz diffusion cells. Inall of the cases, phosphate buffer (pH 5.5) with an addition of 0.1%NaN₃ was used as the preservative agent.

The accumulated permeation rates of vinpocetine are shown in FIG. 1; theindividual measurement points represent the mean value of threeindividual measurements. The results of the tests on the permeation ofvinpocetine are summarised in Table 1.

TABLE 1 Comparison of the permeation rates of vinpocetine achieved withdifferent transdermal therapeutic systems % by weight of the componentsPressure- in the In vitro- Control sensitive Enhancer enhancer skin fluxSystem membrane adhesive component(s) mixture [μg/cm²xh] Example 1Polyurethane Polyacrylate Miglyol type 35 10.9 812 25 dimethyl 25isosorbide 15 Eucalyptol 1-Dodecanol Example 2 PolypropyleneEthylene-vinyl Miglyol type 35 13.0 acetate 812 25 copolymer withDimethyl 25 addition of a isosorbide 15 colophony- Eucalyptol basedadhesive 1-Dodecanol resin Example 3 Polyurethane Polyacrylate Miglyoltype 35 0.426 812 25 Dimethyl 25 isosorbide 15 Ethanol 1-DodecanolExample 4 Polyurethane Polyacrylate Lauryl 100 1.16 lactate ComparativeN/A Polyisobutylene Lauryl 17 1.10 Example 1 lactate

For a transdermal therapeutic system according to Example 1, forexample, it follows from Table 1 that in accordance with the relationQ_(SS)=J_(SS)×A/Cl a transdermal therapeutic system having a releasesurface of 10 cm² would be sufficient to achieve a vinpocetine plasmalevel of 2.5 ng/ml, the quantities Q_(SS), J_(SS), A and Cl having thefollowing meanings:

Q_(SS)=steady state plasma level, in ng/ml;

J_(SS)=in-vitro skin flux, in μg/cm²×h;

A=effective release surface area of the system, in cm²; and

Cl=Clearance (purification rate, amount of plasma per unit of time of acertain active substance) in 1/h; value for vinpocetine taken fromKobayashi, D. et al., Biol. Pharm. Bull., 16, (1993), 254-258).

The cumulated permeation rates of moxonidine are shown in FIG. 2; theindividual measurement points represent the mean value of threeindividual measurements. The results of the tests on the permeation ofmoxonidine are summarised in Table 2.

As shown by a comparison between the experimental results relating tothe transdermal release of moxonidine, a liquid reservoir systemaccording to Example 6 leads to permeation rates which are about 60%below those obtained with a liquid reservoir system according to Example5. FIG. 2 illustrates the synergistic effect of the four enhancercomponents contained in a liquid reservoir system according to Example5.

TABLE 2 Comparison of the permeation rates of moxonidine achieved withdifferent transdermal therapeutic systems % by weight of the componentsPressure- in the In vitro- Control sensitive Enhancer enhancer skin fluxSystem membrane adhesive component(s) mixture [μg/cm²xh] Example 5 Poly-Polyacrylate Miglyol type 812 35 2.79 urethane Dimethyl isosorbide 25Eucalyptol 25 n-Dodecanol 15 Example 6 Poly- Polyacrylate Lauryl lactate35 1.56 urethane Oleic acid 25 Eucalyptol 25 Menthol 15 Comparative0.447 Example 2

The cumulated permeation rates of pergolide are shown in FIG. 3; theindividual measurement points represent the mean value of threeindividual measurements. The results of the tests on the permeation ofpergolide are summarised in Table 3.

As shown by a comparison between the experimental results relating tothe transdermal release of pergolide, a liquid reservoir systemaccording to Example 8 leads to permeation rates which are about 60%below those obtained with a liquid reservoir system according to Example7, which contains only a single permeation enhancer. FIG. 3 illustratesthe synergistic effect of the four enhancer components contained in aliquid reservoir system according to Example 7 as compared to themono-enhancer system eucalyptol (Example 8).

TABLE 3 Comparison of the permeation rates of pergolide achieved withdifferent transdermal therapeutic systems % by weight of the com-ponents Control Pressure- in the In vitro- mem- sensitive Enhancerenhancer skin flux System brane adhesive component(s) mixture [μg/cm²xh]Example 7 Poly- Poly- Miglyol type 35 0.309 urethane acrylate 812 25Dimethyl 25 isosorbide 15 Eucalyptol n-Dodecanol Example 8 Poly- Poly-Eucalyptol 100 0.185 urethane acrylate Comparative 0.165 Example 3

As is shown by a comparison of the experimental results, the liquidreservoir systems according to the invention lead to permeation rateswhich are clearly higher than those obtainable with a matrix transdermaltherapeutic system and which are clearly above the set target.

What has been described above are preferred aspects of the presentinvention. It is of course not possible to describe every conceivablecombination of components or methodologies for purposes of describingthe present invention, but one of ordinary skill in the art willrecognize that many further combinations and permutations of the presentinvention are possible. Accordingly, the present invention is intendedto embrace all such alterations, combinations, modifications, andvariations that fall within the spirit and scope of the appended claims.

We claim:
 1. A transdermal therapeutic system for administering invarying sizes of doses a lipophilic, poorly water-soluble and sparinglyskin-permeable active substance, wherein the active substance possessesa solubility in water of less than 0.3%-wt. and is present in a formselected from the group consisting of a dissolved form and a suspendedform in a multi-component enhancer system for forming an activesubstance-containing preparation, said enhancer system consisting of 4enhancer-components and each component of said multi-component enhancersystem being selected from a different one of the substance groups: a)terpenes in an amount of 25%-wt.; b) cyclic glucitol ethers in an amountof 25%-wt.; c) medium-chain triglycerides of capric and caprylic acidand/or of linoleic acid in an amount of 35%-wt.; and d) longer-chainalcohols having a chain length of 8 or more carbon atoms in an amount of15%-wt.
 2. The transdermal therapeutic system according to claim 1,wherein the enhancer-components are present in a mixing ratio whereinthe proportion of the component used in the lowest dose is at least10%-wt. and the proportion of the most highly dosed component ismaximally 40%-wt., relative to the multi-component enhancer system. 3.The transdermal therapeutic system according to claim 1, wherein theactive substance is selected from the group consisting of vinpocetine,moxonidine, pergolide and the pharmaceutically acceptable salts ofvinpocetine, moxonidine and pergolide.
 4. The transdermal therapeuticsystem according to claim 1, wherein the content of said activesubstance is 0.1 to 50%-wt. relative to the active substance-containingpreparation.
 5. The transdermal therapeutic system according to claim 1,wherein said transdermal therapeutic system further comprises a liquidreservoir system, and wherein said active substance and all of theenhancer-components are present in said liquid reservoir system.
 6. Thetransdermal therapeutic system according to claim 5, wherein said liquidreservoir system comprises a control membrane for controlling therelease of the enhancer-components and of the active substance.
 7. Thetransdermal therapeutic system according to claim 6, wherein saidcontrol membrane consists of a polymer selected from the groupconsisting of polyethylenes, polypropylenes, silicones, polyurethanesand copolymers of ethylene and vinyl acetate.
 8. The transdermaltherapeutic system according to claim 6, wherein said liquid reservoirsystem comprises a pressure-sensitive adhesive layer located below thecontrol membrane, wherein the pressure-sensitive adhesive of saidpressure-sensitive adhesive layer is selected from the group consistingof silicones, acrylates, polyisobutylenes and copolymers of ethylene andvinyl acetate, and wherein the addition of adhesive resins renders saidcopolymers of ethylene and vinyl acetate adhesive.
 9. The transdermaltherapeutic system according to claim 8, wherein said pressure-sensitiveadhesive layer located below the control membrane controls the releaseof the active substance, wherein said control membrane exerts acontrolling effect by the layer thickness.
 10. The transdermaltherapeutic system according to claim 8, wherein adhesive resins areadded to said pressure-sensitive adhesive layer based on copolymers ofethylene and vinyl acetate, and pressure-sensitive adhesive layer basedon copolymer of ethylene and vinyl acetate with the addition of adhesiveresins exerts a controlling effect by the ratio of ethylene to vinylacetate.
 11. The transdermal therapeutic system according to claim 1,wherein said active substance-containing preparation contains additionalauxiliary substances in the form of thickening agents, wherein saidadditional auxiliary substances are selected from the group consistingof mineral oils, wool waxes, polyacrylic acids, high-molecularpolyethylene glycols and finely dispersed silicon dioxide.
 12. Thetransdermal therapeutic system according to claim 1, wherein said activesubstance-containing preparation is present in a form selected from thegroup consisting of a solution, a dispersion, a suspension, a paste anda gel.
 13. The transdermal therapeutic system according to claim 1,wherein said active substance-containing preparation additionallycontains control elements in the form of a retarded release, saidcontrol elements being selected from the group consisting ofcyclodextrins, polyvinyl pyrrolidones and cellulose derivatives.
 14. Thetransdermal therapeutic system according to claim 1, wherein saidmulti-component enhancer system comprises: a) eucalyptol, b) dimethylisosorbide, c) triglycerides of capric and caprylic acid and/or oflinoleic acid, and d) 1 dodecanol.
 15. The transdermal therapeuticsystem according to claim 4, wherein the content of said activesubstance is 5.0 to 25.0%-wt. relative to the activesubstance-containing preparation.
 16. The transdermal therapeutic systemaccording to claim 1, wherein the active substance is vinpocetine or apharmaceutically acceptable salt thereof.
 17. The transdermaltherapeutic system according to claim 1, wherein the active substance ismoxonidine or a pharmaceutically acceptable salt thereof.
 18. Thetransdermal therapeutic system according to claim 1, wherein the activesubstance is selected from the group consisting of vinpocetine,moxonidine, pergolide, pharmaceutically acceptable salts of vinpocetine,pharmaceutically acceptable salts of moxonidine and pharmaceuticallyacceptable salts of pergolide, and wherein said multi-component enhancersystem comprises: (a) an alcoholic monocyclic monoterpene having acyclohexane skeleton as said terpene; (b) dimethyl isosorbide as saidcyclic glucitol ether; (c) medium-chain triglycerides of capric andcaprylic acid and/or of linoleic acid; and (d) 1-dodecanol as saidlonger-chain alcohol.
 19. The transdermal therapeutic system accordingto claim 18, wherein said alcoholic monocyclic monoterpene iseucalyptol.
 20. The transdermal therapeutic system according to claim18, wherein the active substance is vinpocetine or a pharmaceuticallyacceptable salt thereof.
 21. The transdermal therapeutic systemaccording to claim 18, wherein the active substance is moxonidine or apharmaceutically acceptable salt thereof.
 22. The transdermaltherapeutic system according to claim 1, wherein said active substancehas a log P value of above 4, said log P value being the partitioncoefficient of a substance between octanol and water.
 23. Thetransdermal therapeutic system according to claim 1, wherein said activesubstance has a log P value of less than −1, said log P value being thepartition coefficient of a substance between octanol and water.
 24. Atransdermal therapeutic system for administering in varying sizes ofdoses a lipophilic, poorly water-soluble and sparingly skin-permeableactive substance, wherein the active substance possesses a solubility inwater of less than 0.3%-wt. and is present in a form selected from thegroup consisting of a dissolved form and a suspended form in amulti-component enhancer system for forming an activesubstance-containing preparation, said enhancer system comprising 4enhancer-components and each component of said multi-component enhancersystem being selected from a different one of the substance groups: a)terpenes in an amount of 25%-wt.; b) cyclic glucitol ethers in an amountof 25%-wt.; c) medium-chain triglycerides of capric and caprylic acidand/or of linoleic acid in an amount of 35%-wt.; and d) longer-chainalcohols having a chain length of 8 or more carbon atoms in an amount of15%-wt.